. The reported incidence of kidney cancer is increasing faster than almost any other malignancy in the U.S. Approximately 29,000 new cases of RCC, the most common malignancy involving the kidney, were recorded in the U.S. in 1993, with 12,000 deaths resulting directly from the neoplasm. Apart from the association of RCC with cigarette smoking, however, little is known about the aetiology of this disease. Several case-control studies of RCC have shown an increased risk among users of diuretics and non-diuretic antihypertensive medications. Previously published studies, however, have not evaluated risk of RCC in relation to dose and duration of drug use. Furthermore, previous studies have not adequately disentangled the separate, and possibly interactive, effects of hypertension and its treatment on risk of RCC. This proposed population-based case-control study of members of Group Health Cooperative (GHC) is designed to examine the hypothesis that antihypertensive therapy, particularly diuretics, may increase risk of RCC. Specific parameters of antihypertensive drug use to be examined include use (ever), formulation, dosage and duration of use, time since first and last use, and indication for use. Cases will consist of all individuals, age 18-85 years, with primary RCC, diagnosed at GHC between January 1, 1981 and December 31, 1998. A total of 435 RCC cases (290 men and 145 women) are expected to be identified. Controls (1.5 per male case and 4 per female case) without a history of kidney cancer will be randomly selected from computerized GHC membership files and will be frequency matched to each case. Frequency matching criteria will include year of birth (within 5 years), membership status at reference date, GHC clinic attended and length of GHC enrollment. GHC computerized pharmacy records will serve as the primary data source for exposure to diuretics and other antihypertensive medications. Data collection efforts will also include a review of outpatient medical records for ascertaining information on potential confounders. Identifying a large number of RCC cases and controls who can be well characterized with respect to their prior drug exposures affords the opportunity to determine which, if any, of hypertension, diuretic use, or non-diuretic antihypertensive drug use is a risk factor for RCC. Clinical Increased clinical knowledge regarding RCC, hypertension and its treatment may become apparent as a result of this study. The relevance of the proposed investigation is highlighted by the fact that at least 20% of Americans between the ages of 25-74 are on antihypertensive medications; hence, even a small alteration in risk of RCC in relation to antihypertensive medication use could represent a substantial impact on public health.